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Mechanisms of Thyroid Toxicity
Kevin M. CroftonNeurotoxicology DivisionNational Health and Environmental Effects LaboratoryUS Environmental Protection Agency Research Triangle Park NC
Outline
1. Introduction to thyroid hormones2. Effects of perchlorate3. Effects of the disruption of thyroid hormones
Thyroid hyperplasia and neoplasiaDevelopmental abnormalities
4. Uncertainties
National Health and Environmental Effects Laboratory
LiverUDPGTs
T4-Gluc
Biliary Excretion
Hypothalamus-Pituitary-Thyroid-Liver Axis
Plasma/Blood
Free-TH
Bound-TH
PA/TBG
Hypothalamus
Pituitary
Thyroid
TRH
TSH+
+
T3 & T4
T3 & T4
Tissue deiodinase
T4 > T3
National Health and Environmental Effects Laboratory
Iodine and the Thyroid Gland
I
-IT I
-organification
T4 & T3
THYROID GLAND
National Health and Environmental Effects Laboratory
Thyroid Hormone Receptors and Thyroid Response Elements
Target Tissue Cell
T4-TTR
T4T3
deiodinase
Nucleus
T3 Response Element
RXR RAR TR
T3
AGGTCA.....
T3 Responsive Gene
RNA polymerase II
TATA....
National Health and Environmental Effects Laboratory
Targets for Environmental Chemicals
Thyroid Gland uptake processorganification release
Plasma Transport Proteins Tissue Deiodinases Hepatic Glucuronidation and Sulfation
National Health and Environmental Effects Laboratory
In Vitro Thyrotoxicity of Perchlorate125Inhibition of I-Uptake by Perchlorate
Perchlorate Concentration, uM
0 1 10 100 1000
Iod
ine
influ
x,
pm
ol/m
g p
rote
in/m
in (
me
an
±SD
)
0
10
20
30
40
50
60
70
80
(Gerard et al., 1994)
National Health and Environmental Effects Laboratory
14-Day In Vivo Perchlorate Study
Perchlorate dose (mg/kg/day)
0 0.125 0.5 1.25 2.5 5 12.5 25
TS
H C
on
cen
trat
ion
, pg
/dl
0
5
10
15
20
25
30
35
40
45
0 0.125 0.5 1.2 2.5 5 12.5 25
T3
Co
nce
ntr
atio
n, n
g/m
l
0
40
60
80
100
120
140
T4
Co
nce
ntr
atio
n, n
g/d
l
0
2
3
4
5
6
Male Female
0 0.125 0.5 1.2 2.5 5 12.5 25
T3 T4
TSH
(Caldwell et al., 1994)
National Health and Environmental Effects Laboratory
Effect of TH disruption Adult
–Main effect of prolonged depression of TH is upregulation of TSH which leads to thyroid gland hyperplasia
Developmental–Main effect is the disruption of developmental processes
National Health and Environmental Effects Laboratory
Main Symptoms/Effects of Hypothyrodism
Developmentaldelayed reflex ontogenyimpaired fine motor skillsdeaf-mutism, spasticitygait disturbancesmental retardationspeech impairments
transient disruption leads to permanent effects
Adultrun down, slow, depressed, sluggish, cold, tireddryness and brittleness of hairdry and itchy skin, constipationmuscle crampsincreased menstrual flow
transient disruption leads totransient effects
*thyroid tumors in rodents
National Health and Environmental Effects Laboratory
Data Deficiencies Long-term periodic exposures
Perchlorate kinetics Thyroid hormone homeostasis
Effects during development
National Health and Environmental Effects Laboratory
Uncertainties in Risk
1. Animal to Human Extrapolation
2. Age-Dependent Sensitivity
National Health and Environmental Effects Laboratory
Uncertainties Due to Potential Species Differences
AdministeredDose
TargetDose
Effect
AdministeredDose
TargetDose
Effect
Rat
Human
? ?
ADME studies
Mechanistic / SensitivityStudies1. Adult2. Developmental
National Health and Environmental Effects Laboratory
Mechanistic Studies
• Aid to quantitative interspecies extrapolation - basis to extend PBPK model
• Additional developmental studies to evaluate thyroid TH in fetal and post-natal periods
• Determine relative sensitivity of fetal/postnatal thyroid versus adult
• Determine relative sensitivity of rat versus human
National Health and Environmental Effects Laboratory
Do species differences exist? compare rodent and human sensitivitiesusing in vitro techniques
Resolving UncertaintiesMechanistic Studies
Perchlorate Concentration
0 1 10 100 1000
Iod
ine
Up
take
0
10
20
30
40
50
60
70
80
Human (?)
Rat
National Health and Environmental Effects Laboratory
2. Age-Dependent SensitivityDevelopmental effects can be permanent.Is the developing organism more sensitive?
Yes - need to carefully characterizeNo - protection of maternal compartment
Uncertainties in Risk
National Health and Environmental Effects Laboratory
ADME study
• Literature review of perchlorate discharge test
• Protocols proposed to evaluate perchlorate kinetics, iodine inhibition kinetics and thyroid hormone homeostasis
• Basis for development of physiologically-based pharmacokinetic (PBPK) model
National Health and Environmental Effects Laboratory
Resolving Uncertainty - Example2. Age-Dependent Sensitivity
Determine relative sensitivity of fetal/postnatal thyroid versus adult
Determine relative sensitivity of rat versus human
National Health and Environmental Effects Laboratory
National Health and Environmental Effects Laboratory
PBPK Model Schematic
Summary
Facts: Perchlorate cause hypothyroidism
Uncertainties Animal to Human extrapolation Age-dependent senstivity
National Health and Environmental Effects Laboratory
